The present invention relates to drug tablets for oral administration which are adapted to facilitate dissolution of active ingredients which are only slightly soluble in the gastrointestinal tract of warm blooded animals. This results in a substantial increase in the active ingredients biological availability as compared to conventional tablet-formulations. Increased biological availability is of significant importance when dealing with slightly-soluble, high-potency drugs since it provides an opportunity to reduce the daily dosage necessary to produce the desired result.
More specifically, cardiotonic glycosides, such as digoxin and beta-acetyl digoxin are known to be resorbed in the upper regions of the small intestine. Generally, the resorbed quantity of the glycoside is smaller than the quantity of the active ingredient originally ingested.
This resorption loss is due, in part, to the physico-chemical properties of the glycosides as they react with the resorption mechanism of the intestinal mucosa. However, the resorption loss is also due to the form of administration of the active ingredient. More specifically, maximum utilization of resorptive activity of the upper regions of the intestine can only take place when the above-mentioned glycosides exist in solution while present in the duodenum. In other words, undissolved cardiotonic glycosides which pass through the upper intestinal sections are not resorbed as part of the ingested dose thus reducing the biological availability of the active ingredient. Additionally, incomplete resorption results in major fluctuations in the amount of glycoside which, in view of the narrow desirable range of such substances in the body, can be undesirable and even hazardous.
The basic precondition for dissolution of a cardiotonic glycoside given orally in tablet form is disintegration of the tablet upon contact with the gastrointestinal fluid. Once disintegration of the tablet takes place into the primary particles of the compacted mass, the incorporated active ingredients are released and are then available to the dissolution process. The glycoside particles must then dissolve as quickly and as completely as possible to satisfy the requirement of good biological availability.
The rate of dissolution of active ingredients in tablet form can be improved by various known pharmaceuticaltechnological processes such as the addition of solubilizers, embedding in soluble polymers where a moleculardispersed state of the active ingredient is sought (so-called solid solution), and micronization of the active ingredient.
Compared with conventional methods of producing tablets, these methods generally increase production costs. Additionally, when solubilizers and polymeric auxiliary substances are used, problems arise concerning toxicological aspects, and also problems of chemical stability and compatibility between active and auxiliary substances. Obviously, these problems result in an increase in production costs as well.
The object of the present invention is to develop a new galenical tablet composition for slightly soluble active substances, preferably cardiotonic glycosides and, in particular, digoxin, which insures rapid and quantitative dissolution of the active substance upon contact with gastrointestinal fluid thereby providing greater biological availability than can be achieved with conventional tablets.
Another object is to find a production process which requires less expense than the aforementioned known procedures.